Aromatic sulphonamides



United States Patent 3,247,241 AROMATIC SULPHONAMIDES Wilfried Graf,Binningen, near Basel, Erich Schmid, Basel,

and Willy G. Stoll, Bottmingen, Basel-Land, Switzerland, assignors toGeigy Chemical Corporation, Ardsley, N.Y., a corporation of Delaware NoDrawing. Filed Nov. 22, 1961, Ser. No. 154,350 Claims priority,application Switzerland, Nov. 23, 1960, 13,139/ 60 8 Claims. (Cl...260-484) The present invention concerns processes for the production ofnew aromatic sulphonamides as well as the compounds obtained by theseprocesses which have valuable pharmacological properties.

It has surprisingly been found that aromatic sulphonamides of thegeneraliformula wherein R represents hydrogen or an aliphatic acidradical having at most carbon atoms,

R represents a halogen atom, and

R represents hydrogen or a low alkyl radical having at most 3 carbonatoms,

have an excellent diuretic action on peroral or parenteraladministration, whereby the excretion, of sodium ions exceeds that ofpotassium ions to a remarkable and, for therapeuticalpurposes, to a veryfavourable extent. In addition, the compounds of general formula I havevery slight toxicity and are well tolerated.

To produce the new compounds of the general Formula I, water or anoragnic acid of the general Formula HOR (II) in which R, has the meaninggiven above, is reacted with a diazoketone of the general Formula III lRa-NH- O 2 S (III) wherein R and R have the meanings given above, thereaction possibly being performed in the presence of a slight amount ofan inorganic acid, in particular an oxygen acid such as e.g. sulphuricacid, as well as possibly in the presence of slight amounts of heavymetal salts, in particular copper salts such as e.g.copper-(II)-sulphate, and in the presence or absence of an organicsolvent such as e.g. dioxan. The reaction conditions depend on thereactivity of the acid used and generally consist in heating thereaction components for a shorter or longer time. The progress of thereaction is easily followed by watching the nitrogen development.

Possibly, when larger amounts of starting materials are used, onereaction component is added gradually, either in portions orcontinuously, to the other in order to attain a regular development ofnitrogen.

Compounds of the general Formula I are obtained by a further process byreacting a reactive ester of a hydroxy ketone of the general Formula Iawherein R and R have the meanings given above, with a salt of an organicacid of the general Formula II and, if desired, converting the esterobtained into the corresponding hydroxy ketone. This reaction isperformed, for

3,247,241 Patented Apr. 19, 1966 ketone of the general Formula Ia, ahalogen ketone of the general Formula IV RQ NHO2IS (IV) wherein Halrepresents chlorine'or bromine and R and R have the meanings givenabove, with a metal salt of an organic acid of the general Formula II,e.g. with an alkali'metal salt, a silver, mercury or lead salt. Examplesof other reactive esters of hydroxy ketones of the general Formula Iaare the esters of methane sulphonic acid, p-toluene sulphonic acid and2,4-dinitrobenzene sulphonic acid.

In the compounds of the general Formula I and in the correspondingstarting materials, R is, for example, the radical of an aliphaticcarboxylic acid such as acetic acid, formic :acid, propionic acid,butyric acid, isobutyric acid, valeric acid, isovaleric acid, acrylicacid, croton-ic acid, propiolic acid, chloroacetic acid, diehloroaceticacid, fi-chlorocrotonic acid, glycolic acid, lactic acid, glyceric acid,levulinic acid and ethoxyacetic acid.

R is, for example, chlorine, bromine or fluorine, and R is hydrogen, amethyl, ethyl, n-propyl or isopropyl radical.

Diazo ketones, as starting materials of the general Formula II, areproduced for example by reacting the chlorides or bromides of acids ofthe general Formula V R3NHO2S wherein R and R have the meanings givenabove, with diazomethane in a suitable inert organic solvent, e.g. indiethyl ether. Starting materials of the general Formula IV are formed,for example, from the diazo ketones of the general Formula II byreaction with hydrogen chloride or hydrogen bromide in diethyl ether oranother inert organic solvent, or they are formed by reaction of suchdiazo ketones, preferably in the cold, with concentrated hydrochloricacid, e.g. in acetic acid, with liber ation of nitrogen.

The following examples further illustrate the production of the newcompounds according to the invention. Parts are given therein as partsby weight; their relationship to parts by volume is as that of grammesto cubic centimetres. The temperatures are in degrees centigrade.

Example 1 500 parts by volume of a diazomethane solution, produced inthe known manner from 35 parts of nitrosomethyl urea, are poured, within10 minutes, at 15-20" into a solution of 25.5 parts of3-sulphamyl-4-chlorobenzoyl chloride in 1000 parts by volume ofanhydrous ether. After standing for 15 hours at ambient temperature, theexcess diazomethane is distilled off with the ether whereupon3-sulphamyl-4-chloro a diazo-acetophenone remains in crystalline form.

This is dissolved at in 400 parts by volume of dioxan and the solutionis poured, within 10 minutes, into 400 parts of boiling water whichcontains 0.5 part of sulphuric acid. After refluxing for 2 hours, thereaction mixture is evaporated to dryness in vacuo and the crude productis recrystallised from methanol. 3-sulphamyl-4-chloro-a-hydroxy-acetophenone is obtained which melts at 209212 (ondecomposition).

3,247,241 I v 3 i 114 Example 2 7 What is claimed is: "'3-sulpharnyl4-chldroJ' diaio actophnone 3ddti&'*"" 'mrmm subhmmlde'vf the formulaaccording to Example 1 from 25.5 parts of 3-sulphamyl- 4-chlorobenzoylchloride, in 500 parts of glacial acetic 32- CH2 O acid and 0.5 part ofsulphuric acid is refluxed for 1 hour.

The solution is then evaporated to dryness in vacuo and TN the residueis recrystallised from Water. 3-sulphamyl-4 wherein j,chloro-a-acetoxy-acetophenone .is obtained in this way. R is a, memberselected from the grgup consisting of It melts at 183 -l85. hydrogen,and the acyl radical of.a 'n aliphatic car- In an analogous manner, onusing propionic acid in- 10 boxylic acid selected from the groupconsisting of stead of acetic acid, 3-sulphamyl-4chloro-a-propionyloxyacetifi; acid, formic acid, P P Q acidibutyficacid, acetophenone (M.P. 149-450") is obtained, on using isoblltyficacid, Valerie acid, isovalefic acid, acrylic chloroacetic acidtwithoutthe addition of sulphuric acid), acid, crotonic acid, propiolic .acid,chloroacetic acid, 3- sulphamyl-4-chloro ufchlor'oacetoxy acetophenone 1dichlomacetic acid, flon i.g YO (M.P. 163465") is obtained, on using'butyric acid, 3- 5 acid, lactic ci g y i a i levuliniciand hxysulphamyl-4-chloroa butyryloxy acetophenone (M.P. acetic acid, I v V124126) is' obtained, and on using isovaleric acid, 3- 2 is a memberselected from the group consisting ofsulphamyl-4-chlorq-a-isovaleroyloxy-acetophenone (M.P. P i116, Chiofineand b and 133-135") i obt j d V 20 R is a member selected from the groupconsisting of hydrogen and alkyl of at most 3 carbon atoms. Example 3 2.3-sulphamoyl-4-chloro-u-hydroxyacetophenone.

3-sulphamyl-4-chloro-a diazo-acetophenone produced 3.3-sulphamoyl-4-chloro-a-acetoxyacetopheuone. as described in Example 1,is suspended in 100 parts of v 4. 3-sulphamoyl-4- chloroa-propionyloxyacetophelactic acid'and the suspension is heated to 70.The tern- 5 none. perature is kept at 70 until, after about 20-30minutes, 5. 3-sulpharn0yl-4-chloro 0c chloroacetoxyacetophethe nitrogendevelopemnt is complete'and a clear solution nonci x is obtained. Thereaction mixture is then cooled at 0 6.3-sl1lpharnoyl-4-chloro-a-butyryloxyacetophenone; and 400 parts of iceWater are added. The oily, rude 7.3-sulphamoyl-4-chloro-a-isovaleryloxyactophenone.

product which separates, crystallises after a few hours. 30 3- 3-111pham0y1 4-chloro-oc-lactoyloxyacetophenone. It is taken up in ether,the solution is dried with Siccon 1 and the ether is evaporated off. Thecrystalline residue is NO references cuedrecrystallised from n-arnylalcohol. In this way, 3-sulphamyl-4-chloro-m-lactoyloxy-acetophenonewhich melts LORRAINE WEINBERGER Pnmary Emmmen at l98199 is obtained.DANIEL D. HORWITZ, LEON ZITVER, Examiners.

1. AN AROMATIC SULPHONAMIDE OF THE FORMULA 